Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection

Department of Pathology, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 06/2011; 208(6):1163-77. DOI: 10.1084/jem.20102555
Source: PubMed

ABSTRACT Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor-driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12-induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.

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Available from: Fong-Fu Hsu, Jul 28, 2015
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    • "Indeed, endogenous cell surface expression levels of MR1 are very low, suggesting that a bacterial Ag is required to stabilize MR1 and/or increase its MR1 presentation (Chua et al., 2011). Alternatively, it is possible that bacterial infection may indirectly result in MAIT cell activation through activation of Toll-like receptors or other innate pathways, as occurs for NKT cells (Brigl et al., 2011). However, this seems unlikely for MAIT cells, as previous studies indicate that their activation can occur independently of My88D, TRIF, Nod1,-2, N1rp3, Asc, Ips TLR2, and TLR4 (Gold et al., 2010; Le Bourhis et al., 2010). "
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    • "iNKT cells are known to be able to secrete a variety of different cytokines, including both Th1 and Th2 types (Venkataswamy and Porcelli, 2010) and can respond to CD1d presenting lipids from both exogenous and endogenous sources. The strength of the antigenic signal delivered through the iNKT TCR and the presence of other cytokines (i.e., IL-12; Brigl et al, 2003) during iNKT cell stimulation have been shown to be key factors influencing the cytokines produced by iNKT cells (Wang et al, 2008; Bricard et al, 2010; Brigl et al, 2011). Much of the work on iNKT cell recognition has been focussed on bacterial glycolipids, however, there is increasing evidence that recognition of endogenous antigens, or iNKT cell autoreactivity, contributes to their function in the immune response and some of those selfantigens have been characterized (Zhou et al, 2004b; Paget et al, 2007; Salio et al, 2007; Brennan et al, 2011). "
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